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- Title
GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein.
- Authors
Jing Cheng; Klei, Linda R.; Hubel, Nathaniel E.; Ming Zhang; Schairer, Rebekka; Maurer, Lisa M.; Klei, Hanna B.; Kang, Heejae; Concel, Vincent J.; Delekta, Phillip C.; Dang, Eric V.; Mintz, Michelle A.; Baens, Mathijs; Cyster, Jason G.; Parameswaran, Narayanan; Thome, Margot; Lucas, Peter C.; McAllister-Lucas, Linda M.; Cheng, Jing; Zhang, Ming
- Abstract
Antigen receptor-dependent (AgR-dependent) stimulation of the NF-κB transcription factor in lymphocytes is a required event during adaptive immune response, but dysregulated activation of this signaling pathway can lead to lymphoma. AgR stimulation promotes assembly of the CARMA1-BCL10-MALT1 complex, wherein MALT1 acts as (a) a scaffold to recruit components of the canonical NF-κB machinery and (b) a protease to cleave and inactivate specific substrates, including negative regulators of NF-κB. In multiple lymphoma subtypes, malignant B cells hijack AgR signaling pathways to promote their own growth and survival, and inhibiting MALT1 reduces the viability and growth of these tumors. As such, MALT1 has emerged as a potential pharmaceutical target. Here, we identified G protein-coupled receptor kinase 2 (GRK2) as a new MALT1-interacting protein. We demonstrated that GRK2 binds the death domain of MALT1 and inhibits MALT1 scaffolding and proteolytic activities. We found that lower GRK2 levels in activated B cell-type diffuse large B cell lymphoma (ABC-DLBCL) are associated with reduced survival, and that GRK2 knockdown enhances ABC-DLBCL tumor growth in vitro and in vivo. Together, our findings suggest that GRK2 can function as a tumor suppressor by inhibiting MALT1 and provide a roadmap for developing new strategies to inhibit MALT1-dependent lymphomagenesis.
- Subjects
G proteins; G protein coupled receptors; LYMPHOKINES; B cells; TUMOR growth; TRANSCRIPTION factors; PROTEIN metabolism; PROTEINS; RESEARCH; CARCINOGENESIS; ANIMAL experimentation; RESEARCH methodology; B cell lymphoma; EVALUATION research; MEDICAL cooperation; COMPARATIVE studies; RESEARCH funding; MICE; METABOLISM
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 2, p1036
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI97040